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Reliability, Repeatability, and Reproducibility of Pulmonary Transit Time Assessment by Contrast Enhanced Echocardiography Ingeborg H

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Reliability, Repeatability, and Reproducibility of Pulmonary Transit Time Assessment by Contrast Enhanced Echocardiography Ingeborg H Herold et al. Cardiovascular Ultrasound (2016) 14:1 DOI 10.1186/s12947-015-0044-1 RESEARCH Open Access Reliability, repeatability, and reproducibility of pulmonary transit time assessment by contrast enhanced echocardiography Ingeborg H. F. Herold1*, Salvatore Saporito2, R. Arthur Bouwman1, Patrick Houthuizen3, Hans C. van Assen2, Massimo Mischi2 and Hendrikus H. M. Korsten1,2 Abstract Background: The aim of this study is to investigate the inter and intra-rater reliability, repeatability, and reproducibility of pulmonary transit time (PTT) measurement in patients using contrast enhanced ultrasound (CEUS), as an indirect measure of preload and left ventricular function. Methods: Mean transit times (MTT) were measured by drawing a region of interest (ROI) in right and left cardiac ventricle in the CEUS loops. Acoustic intensity dilution curves were obtained from the ROIs. MTTs were calculated by applying model-based fitting on the dilution curves. PTT was calculated as the difference of the MTTs. Eight raters with different levels of experience measured the PTT (time moment 1) and repeated the measurement within a week (time moment 2). Reliability and agreement were assessed using intra-class correlations (ICC) and Bland-Altman analysis. Repeatability was tested by estimating the variance of means (ANOVA) of three injections in each patient at different doses. Reproducibility was tested by the ICC of the two time moments. Results: Fifteen patients with heart failure were included. The mean PTT was 11.8 ± 3.1 s at time moment 1 and 11.7 ± 2.9 s at time moment 2. The inter-rater reliability for PTT was excellent (ICC = 0.94). The intra-rater reliability per rater was between 0.81–0.99. Bland-Altman analysis revealed a bias of 0.10 s within the rater groups. Reproducibility for PTT showed an ICC = 0.94 between the two time moments. ANOVA showed no significant difference between the means of the three different doses F = 0.048 (P = 0.95). The mean and standard deviation for PTT estimates at three different doses was 11.6 ± 3.3 s. Conclusions: PTT estimation using CEUS shows a high inter- and intra-rater reliability, repeatability at three different doses, and reproducibility by ROI drawing. This makes the minimally invasive PTT measurement using contrast echocardiography ready for clinical evaluation in patients with heart failure and for preload estimation. Keywords: Contrast enhanced ultrasound, Echocardiography, Indicator dilution technique, Intra-class correlation, Mean transit time, Pulmonary transit time, Reliability Background estimation [1–3]. This technique uses transthoracic echo- Pulmonary blood volume quantification by transpulmonary cardiography (TTE) to visualize the transcardiac passage of dilution analysis is an essential part of the hemodynamic an ultrasound contrast-agent (UCA) bolus injected in a evaluation to guide fluid management in anesthesia and peripheral vein. Indicator dilution curves (IDCs) are then intensive care practice. Recently, contrast-enhanced ultra- derived from the acoustic backscatter of the UCA bolus in sound (CEUS) has been proposed as a minimally-invasive, the four heart chambers. The mean transit time (MTT) of alternative method for pulmonary transit time (PTT) these acoustic IDCs can be estimated by different methods. The most frequently used methods in clinical practice are based on assessment of the “peaks” of the IDCs or “frame * Correspondence: [email protected] 1Department of Anesthesiology and Intensive-Care, Catharina Hospital counting” of the appearance of the first bubbles in the Eindhoven, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands heart chambers [3–5].WeestimatetheMTTbymodel Full list of author information is available at the end of the article © 2015 Herold et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Herold et al. Cardiovascular Ultrasound (2016) 14:1 Page 2 of 9 fitting using the local density random walk (LDRW) model, positioned in left lateral position. The UCA was admin- which takes into account the Brownian motion of the bolus istered according to our hospital CEUS protocol. All contrast in the blood stream through the pulmonary contrast-enhanced TTE imaging was performed by an vessels and heart chambers [1, 2, 6, 7]. experienced imaging-cardiologist (PH) using an iE33 In previous studies, we demonstrated that volume ultrasound scanner equipped with a S5-1 transducer estimation by CEUS, resulting from the multiplication of (Philips Healthcare, Andover, MA, USA). Four chamber the flow by the PTT (i.e. the difference between the apical views were obtained using harmonic imaging at MTTs of the left atrium and the right ventricle (RV)), 1.3–2.6 MHz, a low mechanical index (MI) of 0.19 to showed excellent agreement with the actual volumes, reduce microbubble destruction, a frame rate of 23 Hz, both in-vitro and in-vivo [2, 6]. Moreover, it showed and a dynamic range of 50 dB with linear post- even better accuracy than transpulmonary thermodilu- processing. tion volume estimation [1, 8]. However, the reliability of SonoVue® (Bracco SpA, Milan, Italy) consisting of PTTs derived with CEUS and the LDRW in-vivo has not microbubbles with a SF6 gas enclosed in a phospholipids been established. Therefore, in this study we investigated monolayer shell was used as UCA. These microbubbles, the reliability and reproducibility of the assessment of PTT with an average size of 3 to 9 μm, pass the pulmonary with CEUS using the LDRW model, in patients referred circulation and can be visualized in both RV and LV [9]. for cardiac resynchronization therapy. We also investi- After a peripheral bolus injection, the passage of micro- gated the effect of different UCA doses on the PTT bubbles through the right and left heart was visualized measurement. In addition, to evaluate the complexity of from a four chamber apical view without breath-hold by the PTT assessment by means of CEUS-recording selecting the proper probe angle, to minimize movement analysis, PTT was also estimated by non-physicians. If artifacts. We diluted 1 ml SonoVue® in saline (1:400, also non-physicians can obtain reliable measurements, 1:200, and 1:100) and injected a bolus of 10 ml of the this would imply a fast learning curve, favoring the solution. Three different CEUS loops were recorded in method adoption in clinical practice. Therefore, our consistent consecutive order. The injections were per- second objective was to evaluate the reliability and formed in a reproducible way as a manual instantaneous agreement between PTT measurements obtained by bolus and each dose was administered as soon as the physicians and non-physicians. recirculating microbubbles disappeared from the left ventricle. These are doses lower than those used for left Methods ventricular opacification [10], but give good opacification Patients of the ventricles while providing an approximately linear As per local hospital protocol, all patients referred for relationship between the UCA concentration and the cardiac resynchronization therapy underwent extensive measured acoustic intensity; the latter is a prerequisite echocardiographic evaluation including contrast enhanced for application of the indicator dilution theory [1, 2]. ejection fraction measurements. This patient population Reliability was tested by eight raters: four physicians scheduled for contrast enhanced TTE to assess ejection who were all experienced with echocardiography but fraction and eligibility were included for this observational with different levels of experience with measuring MTT study. In general, these were patients with symptomatic (one rater was experienced (IH), one rater had some heart failure, a decreased ejection fraction, and QRS- experience (HK), and two had experience in endocardial widening by more than 120 ms. Patients were excluded in border tracing (PH, JD)), and four technicians from the case of atrial fibrillation, an acute coronary syndrome Eindhoven University of Technology of whom three within the past three months, a known allergy to sulphur- were inexperienced with echocardiography and MTT hexafluoride, or a poor acoustic window (impossibility to (HA, GW, AG) and one was an expert in the field visualize an apical 4-chamber view). The Institutional (MM). All raters received a detailed guide for drawing Review Board of the Catharina Hospital Eindhoven ROIs in both RV and LV at the two time moments. Each approved the study, and written informed consent for use rater received the same fifteen anonymized ultrasound of echocardiography data for scientific purposes was apical four chamber view loops following the injection obtained from all subjects. of a SonoVue® in saline bolus at a dilution of 1:200 (Fig. 1). The raters were instructed to draw regions of Measurement protocol interest (ROIs) independently within the endocardial bor- Patients referred for a left ventricle (LV) dyssynchrony ders of the RV and LV throughout the cardiac cycle; no evaluation received a standard of care CEUS echocardi- specified ROI surface was predefined (Additional file 1). ography according to our hospital protocol (Fig. 1). In ROI position was fixed over all the frames. Movement of all patients, an 18-gauge catheter was inserted in a borders or valve structures within the ROI will create arti- peripheral vein of the fore-arm and the patient was facts in the IDC. Therefore, the instructions emphasized Herold et al. Cardiovascular Ultrasound (2016) 14:1 Page 3 of 9 Fig. 1 The passage of a bolus of SonoVue® through the right atrium and ventricle (panel b) and left atrium and ventricle (panel c). ROIs are drawn in the right and left ventricle (not shown, see Additional file 1).
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